Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells

Amplification or overexpression of HER-2/neu in cancer cells confers resistance to apoptosis and promotes cell growth. The cellular localization of p21(Cip1/WAF1) has been proposed to be critical either in promoting cell survival or in inhibiting cell growth. Here we show that HER-2/neu-mediated cell growth requires the activation of Akt, which associates with p21(Cip1/WAF1) and phosphorylates it at threonine 145, resulting in cytoplasmic localization of p21(Cip1/WAF1). Furthermore, blocking the Akt pathway with a dominant-negative Akt mutant restores the nuclear localization and cell-growth-inhibiting activity of p21(Cip1/WAF1). Our results indicate that HER-2/neu induces cytoplasmic localization of p21(Cip1/WAF1) through activation of Akt to promote cell growth, which may have implications for the oncogenic activity of HER-2/neu and Akt.